: The long term objectives of this research are to define the biochemical and genetic events that characterize the bacterial colonization of animal epithelial tissue. The benign, symbiotic infection of the light-emitting organ of the squid Euprymna scolopes by the luminous bacterium Vibrio fischeri will be used as a model system by which to address these objectives. Recent investigations of this association have centered on the events characterizing its initiation, establishment, and accommodation during the first 48 hours of the symbiotic infection of newly hatched juvenile squids. The experimental approaches described herein use bacterial mutants and host morphogenic indicators to manipulate and assay the complex succession of signalling and responses through which the host and bacterium communicate during these stages of the colonization process. The proposed research plan integrates 3 specific aims: (1) to determine how tissue tropism is facilitated by the host, and exploited by V. fischeri cells; (2) to investigate the role of host phagocytes in the association; and, (3) to define how the products of the luxAIR genes mediate both the swelling of crypt epithelial cells and the achievement of normal colonization levels by the bacteria. It is expected that the results of this research will provide insight into how newly discovered host-derived, mucus-like structures facilitate V. fischeri migration to internal host tissues, how the colonizing bacteria specifically evade the host immune system, and whether the oxygenase activity of their luciferase evokes both host tissue morphogenesis and nutrient provision. This system serves as a model of both benign and pathogenic Vibrio infection and, perhaps, of the evolution of the virulence state in vibrios. Specifically, the identification of bacterial determinants that potentiate light organ symbiosis has already revealed convergences with known V. cholerae virulence factors, and continued efforts may promote the discovery of as yet undescribed ones. The work proposed here will also provide new information about the mechanisms by which specific, stable colonizations of clams, snails, squid and their relatives may serve as environmental reservoirs for human pathogenic Vibrio species.